Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study

Background For some people with migraine, despite taking greater amounts of acute headache medication (AHM), they develop an increase in monthly headache days. This cycle of increasing headache days, and in turn AHM use, can lead to a secondary headache disorder called medication-overuse headache (MOH). Preventive medications can prevent migraine from occurring and reduce reliance on AHMs, thereby preventing the cycle of MOH. This study was performed to evaluate the efficacy and safety of eptinezumab to prevent migraine/headache in a mainly Asian patient population with a dual diagnosis of chronic migraine and MOH. Methods SUNLIGHT was a phase 3, multicenter, double-blind, parallel-group, placebo-controlled trial. Patients aged 18−75 years with ≥ 8 migraine days/month and a diagnosis of MOH were randomly allocated (1:1) to one of two treatment groups: eptinezumab 100 mg or placebo. Monthly migraine days (MMDs) were captured using a daily electronic diary; the change from baseline in the number of MMDs over Weeks 1−12 was the primary efficacy endpoint. Results Patients were randomized to eptinezumab 100 mg (n = 93) or placebo (n = 100). Over Weeks 1−12, eptinezumab reduced mean MMDs more than placebo (difference between treatments was -1.2; p = 0.1484). Differences between treatment groups with p-values below 0.05 favoring eptinezumab were observed in 3 out of the 6 key secondary endpoints. Conclusion All endpoints numerically favored eptinezumab treatment when compared to placebo; however, this study did not meet its primary endpoint and is therefore negative. No new safety signals were identified in this study, like previous reports that confirmed the safety and tolerability of eptinezumab treatment. Trial registration ClinicalTrials.gov identifier: NCT04772742 (26/02/2021). Supplementary Information The online version contains supplementary material available at 10.1186/s12883-023-03477-z.


Patient-reported outcomes
6-item Headache Impact Test (HIT-6): HIT-6 (v1.0) provides patients with a way to describe the impacts of headache on normal daily function.The brief questionnaire consists of six scored questions, each with the following choices for response: "never" (6 points), "rarely" (8 points), "sometimes" (10 points), "very often" (11 points), and "always" (13 points).The total score is calculated by adding the points associated with each response, providing a total score that ranges from 36 to 78.From these scores, the severity of headache effect on daily life is determined [1].
Migraine-Specific Quality of Life Questionnaire (MSQ): MSQ (v2.1) assesses the impact of migraine on patient quality of life based on three categories of assessment: role function restrictive, role function preventive, and emotional function.For each of the fourteen total items spanning the three categories, eac h item is scored using a scale from 1 to 6, and subsequent raw scores are transformed to a scale ranging from 0 to 100, with higher scores indicating better patient quality of life [2][3][4].
EQ-5D-5L Visual Analogue Scale (VAS): The EQ-5D-5L assesses patient well-being using the descriptive categories of mobility, self-care, usual activities, pain/discomfort, and depression/anxiety along with a visual analogue scale (VAS).The brief assessment describes well-being using a scale ranging from the worst imaginable health state (score 0) to the best imaginable health state (score 100) [5].
Work Productivity and Activity Impairment: Migraine (WPAI:M): Patients use the WPAI:M assessment to obtain a measurement of their work productivity and activity impairment in the context of their migraine-related health problems.The six-item questionnaire explores the impact of migraine on life such as the number of hours worked, the numbers of working hours missed, effects on work productivity, and effects on normal daily activities outside of work.Lower scores indicate a better quality of life compared to higher scores [6].

Primary Objective
To evaluate the efficacy of eptinezumab for the prevention of migraine and medication-overuse headache (MOH) Primary endpoint -Change from baseline in the number of monthly migraine days (MMDs) (Weeks 1-12) Key secondary endpoints -Change from baseline in MMDs with use of acute medication (Weeks 1-12) -Response: ≥50% reduction from baseline in MMDs (Weeks 1-12) -Migraine on the day after dosing (Day 1) -Response: ≥75% reduction from baseline in MMDs (Weeks 1-4) -Change from baseline in the number of monthly headache days (MHDs) (Weeks 1-12) -Response: ≥75% reduction from baseline in MMDs (Weeks 1-12) Secondary endpoints -Response: ≥75% reduction from baseline in MHDs (Weeks 1-12) -Response: ≥75% reduction from baseline in MHDs (Weeks 1-4) -Change from baseline in the number of MHDs with use of acute medication (Weeks 1-12) -Change from baseline in the proportion of migraine attacks with severe pain intensity (Weeks 1-12) -Change from baseline in the proportion of headache episodes with severe pain intensity (Weeks 1-12) -Patient Global Impression of Change (PGIC) score at Week 12 -Change score at Week 12 in patient-identified most bothersome symptom (PI-MBS; as reported at Screening) Exploratory endpoints -Response: 100% reduction from baseline in MMDs (average of 4-weeks results over Weeks 1-12) -Response: 100% reduction from baseline in MHDs (average of 4-weeks results over Weeks 1-12) -Change from baseline in monthly number of migraine attacks (Weeks 1-12) -Change from baseline in monthly number of headache episodes (Weeks 1-12) -Change from baseline in monthly days with use of acute migraine medication (Weeks 1-12) -Change from baseline in monthly days with use of ergotamine (Weeks 1-12, Weeks 1-4, Weeks 5-8, Weeks 9-12); similar endpoints defined for use of triptans, analgesics, opioids, combination analgesics, traditional Chinese medicines (TCMs), antiemetics, analginum, antipyrine, and tolfenamic acid -Change from baseline in monthly days with use of nonopioid analgesics (defined as any of the following 4 categories of non-opioid analgesics collected in the eDiary: analgesic, analginum, antipyrine, and tolfenamic acid medications) (Weeks 1-12, Weeks 1-4, Weeks 5-8, Weeks 9-12)

*Supplemental Figure 2 .Supplemental Figure 3 .Supplemental Figure 4 .Supplemental Figure 5 .Supplemental Figure 6 .
2 (-8.0 to 1.5) 0.1756 Change from baseline in MMDs in ≤35 years of age (Weeks 1-12) Number of patients Change in mean from baseline (SE) Difference from placebo (95% CI) Change from baseline in MMDs in >35 years of age (Weeks 1-12) Number of patients Change in mean from baseline (SE) Difference from placebo (95% CI) Number of patients Change in mean from baseline (SE) Difference from placebo (95% CI) p-value vs placebo 58 -6.3 (0.91) 54 -7.2 (0.98) -0.9 (-3.4 to 1.5) Note: The Asian subpopulation was composed of patients from Mainland China, Taiwan, and Republic of Korea.CI, confidence interval; FAS, full analysis set; MHD, monthly headache days; MMD, monthly migraine days; SE, standard error.Statistical testing hierarchy for primary and key secondary endpoints Statistical testing was done hierarchically, in a number of steps.For each step, the treatment effect was tested on a 5% significance level and testing only continued to the next step if all prior effects in the hierarchy were found to have p-values below the specified significance level.MMDs, monthly migraine days; MHDs, monthly headache days; MRR, migraine responder rate.Number of previous preventive treatment failures (FAS) FAS, full analysis set.Yu, Zhou, Luo, et al.Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.BMC Neurology.2023.Page 11 of 15 Change from baseline in MMDs with AHM use over (A) Weeks 1-12 and (B) 4-week intervals (FAS)The estimated means, mean differences from placebo, and 95% confidence intervals are from an MMRM with month (Weeks 1-4, Weeks 5-8, Weeks 9-12), region, stratification factor (MHDs at baseline: <20/≥20) and treatment as factors, baseline score as a continuous covariate, treatment-by-month interaction, baseline score-by-month interaction, and stratum-by-month interaction.From the MMRM, estimates and tests across multiple 4-week intervals are computed via SAS using equal weights for each 4-week interval.Data represent mean ± standard error.AHM, acute headache medication; FAS, full analysis set; MHDs, monthly headache days; MMDs, monthly migraine days; MMRM, mixed model for repeated measures; SAS, statistical analysis system.Yu, Zhou, Luo, et al.Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.BMC Neurology.2023.Page 12 of 15 Percentage of patients with migraine on the day after the first dose (FAS)The p-values are computed using extended Cochran-Mantel-Haenszel test, adjusting for the stratification factor (monthly headache days at baseline <20/≥20).Baseline is the average percentage of patients with migraine across the first 28 days.The percentage of patients with a migraine on the day after first dosing is derived based on available eDiary data on Day 1, unless the eDiary data on Day 1 are missing.In that case, the migraine rate for the patient is imputed.n indicates the number of subjects in the analysis at the relevant timepoint.FAS, full analysis set.Yu, Zhou, Luo, et al.Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.BMC Neurology.2023.Page 13 of 15 Analysis of (A) proportion of patients achieving a 5-point reduction in HIT-6 total score at Week 12 and (B) change from baseline in MSQ subscores at Week 12 (FAS) (A) Data represent mean ± standard error.n.s., not significant vs placebo.(B) The model includes the following fixed effects: visit, region, stratification factor (monthly headache days at baseline: <20/≥20), and treatment as factors, baseline MSQ v2.1 subscores as a continuous covariate, baseline score-by-visit interaction, treatment-by-visit interaction, and stratum-by-visit interaction.Data represent mean ± standard error.FAS, full analysis set; HIT-6, 6-item Headache Impact Test; MSQ, Migraine-Specific Quality of Life Questionnaire, v2.1.

Table 2 .
-Shifts in the use of medication from above/below the medication overuse (MO) threshold at baseline to above/below the MO threshold at Weeks 1-4, Weeks 5-8, and Week 9-12; the MO threshold for each class of drugs is presented below: Change from baseline to Week 12 in the health-related quality of life (EQ-5D-5L Visual Analogue Scale [VAS]) score -Baseline and Week 12 in health care resources utilization (HCRU) -Change from baseline to Week 12 in the Migraine Work Productivity and Activity Impairment Questionnaire (WPAI:M) subscores Analysis of change from baseline in MMDs (Weeks 1-12) across various subgroups (FAS)